ES2728975T3 - Intravaginal drug delivery device comprising a polyurethane copolymer - Google Patents

Abstract

An intravaginal drug delivery device comprising at least two pharmaceutically active substances, in which the pharmaceutically active substances have contrasting hydrophilicity, combined with a polyurethane copolymer, in which the copolymer has the structure according to formula (I): ** Formula ** in which, SME1 and SME2 may be the same or different and indicate a surface modifying end group, having a number average molecular weight ranging from 200 to 8000 g / mol, connected to the polymer through a bond of urethane or urea resulting from the reaction of an amine or alcohol terminated surface modifying end group with an isocyanate group, wherein SME1 and SME2 are methylpolyethylene glycol; SS1, SS2 and SS3 indicate soft segments, where SS1 is a polyetherdiol selected from polyethylene oxide (PEO) diol, poly (tetramethylene oxide) (PTMO) diol, poly (hexamethylene oxide) diol (PHMO) , poly (propylene oxide) (PPO) diol, diol copolymer of ethylene glycol and propylene glycol (PEG-co-PPO), and mixtures thereof; SS2 is a hydroxyl or amine terminated silicone polymer having a number average molecular weight ranging from 500 to 5000 g / mol; and SS3 is a soft segment selected from polycarbonate diol and polyester diol, and mixtures thereof; HS indicates a hard segment prepared from the reaction of one or more diisocyanates and one or more chain extenders, wherein the diisocyanate is selected from the group consisting of hexamethylene diisocyanate (HMDI) and isophorone diisocyanate (IPDI) and combinations thereof; x, y, and z are the same or different and each is an integer equal to or greater than zero and at least one of x, y and z is not zero; and wherein the copolymer has a number average molecular weight ranging from 50,000 to 350,000 g / mol.

Description

DESCRIPTION

Intravaginal drug delivery device comprising a polyurethane copolymer

Background of the invention

The present invention relates to intravaginal drug delivery devices made of polyurethane copolymers and to the administration of one or more pharmaceutically active substances to a patient in need.

Drug delivery devices are specialized tools for the contribution of a drug or therapeutic agent through a specific route of administration. These devices are used as part of one or more medical treatments. Examples of drug delivery devices include, but are not limited to, cardiovascular devices, ophthalmic devices, antiviral devices, dialysis devices, contraceptive devices, endovascular prostheses that elude drugs, a catheter, transdermal devices and / or intrauterine devices.

Drug delivery devices, such as intravaginal drug delivery devices, including intravaginal rings (IVRs), are typically formed of biocompatible polymers and contain a drug released by diffusion through the polymer matrix. IVR devices can be inserted into the vaginal cavity and the drug can be absorbed by the surrounding body fluid through the vaginal tissue.

Poly (ethylene-co-vinyl acetate) or ethylene-vinyl acetate (EVA) (used, e.g., in NuvaRing) and poly (dimethylsiloxane) or silicone (used, e.g., in Estring, Femring and a progesterone release ring from the Population Council) are currently commercially exploited for IVRs. Compared to poly (ethylene vinyl acetate) or ethylene vinyl acetate (EVA), silicone is limited by a lower mechanical toughness. Therefore, silicone IVRs are manufactured with larger transverse diameters to achieve the retractable forces required for retention in the vaginal cavity, which may affect the user's ability to accept the ring. On the other hand, the manufacturing costs associated with these IVRs are considerable. It has been found that both EVA and silicone are particularly useful for the release of a steroid that is a substantially water insoluble drug.

Intravaginal rings containing polyurethane have been described (See Gupta, Kavita M. et al. Journal of Pharmaceutical Sciences (2008), 97 (10), 4228-4239 and WO2009094573. The known polyurethane-containing IVRs are IVRs containing a ring only In addition, segmented polyurethane IVRs are described in WO2009003125 and WO2009094573.

In addition, the use of polyurethanes for drug delivery devices has been limited in part due to the high processing temperatures required for polyurethanes. These temperatures are often too high for thermolabile drugs.

It has also been found that EVA and silicone, which with both hydrophobic polymers, are not capable of providing a desired release rate for hydrophilic drugs. Until now, an intravaginal ring has not been developed for the co-contribution of drugs with different hydrophilicity.

This deficiency is remedied by the intravaginal drug delivery devices now disclosed. Drug delivery devices, including intravaginal rings, comprising polyurethane copolymers are provided.

Unlike drug delivery devices according to the prior art, the present drug delivery devices can provide adequate release rates for multiple drugs.

Another advantage of the drug delivery devices according to the invention is that the devices comprise a biostable polymer, which is used as a matrix to disperse or dissolve the drug therein.

A further advantage of the drug delivery devices according to the invention is that the release characteristics of the polyurethane in the drug delivery device can be adapted to fit a range of suitable pharmaceutically active substances that are to be provided from the product of contribution of drugs. An additional advantage is that polyurethane copolymers comprised in the drug delivery device may have a decrease in processing temperatures.

An additional advantage is that the polyurethane copolymer comprised in the drug delivery device has an adjustable permeability to the pharmaceutical active compounds that diffuse through the matrix polymeric This permeability depends on the characteristics of the polymer matrix, such as the hydrophilicity of the various blocks or segments of the copolymer.

Description of the invention

The present invention relates to drug delivery devices comprising at least two pharmaceutically active substances, wherein the pharmaceutically active substances have proven hydrophilicity, combined with a polyurethane copolymer.

The polyurethane copolymers in the drug delivery device according to the invention are copolymers with a structure according to formula I:

in which,

SME1 and SME2 may be the same or different and indicate a surface modifying end group, which has a number average molecular weight ranging from 200 to 8000 g / mol, connected to the polymer through a urethane or urea bond resulting from the reaction of a surface modifying end group terminated in amine or alcohol with an isocyanate group, wherein SME1 and SME2 are methylpolyethylene glycol;

SS1, SS2 and SS3 indicate soft segments, in which

551 is a polyetherdiol selected from poly (ethylene oxide) (PEO) diol, poly (tetramethylene oxide) (PTMO) diol, poly (hexamethylene oxide) diol (PHMO), poly (propylene oxide) (PPO) diol, ethylene glycol and propylene glycol diol copolymer (PEG-co-PPO), and mixtures thereof;

552 is a silicone polymer terminated in hydroxyl or amine having a number average molecular weight ranging from 500 to 5000 g / mol; Y

553 is a soft segment selected from polycarbonate diol and polyester ether, and mixtures thereof;

HS indicates a hard segment prepared from the reaction of one or more diisocyanates and one or more chain extenders, wherein the diisocyanate is selected from the group consisting of hexamethylene diisocyanate (HMDI) and isophorone diisocyanate (IPDI) and combinations thereof;

x, y and z are the same or different and each is an integer equal to or greater than zero and at least one of x, y and z is not zero; Y

wherein the copolymer has a number average molecular weight ranging from 50,000 to 350,000 g / mol.

The drug delivery devices according to the invention comprise at least two pharmaceutically active substances, wherein the pharmaceutically active substances have proven hydrophilicity. Pharmaceutically active substances that can be incorporated into the drug delivery devices comprising the copolymers include microbicides, contraceptive agents, estrogen receptor modulators, postmenopausal hormone, antiretroviral agents, anticancer agents, therapeutics, hormones, and combinations thereof. Examples of hydrophobic pharmaceutically active substances include, but are not limited to, dapivirine, UC781, valdecoxib, allopurinol, acetohexamide, benzthiazide, chlorpromazine, chlordiazepoxide, haloperidol, indomethacin, lorazepam, methoxsalen, methylprednisolone, nifedipine, oxazepam, oxyphenbutazone, prednisone, prednisolone, pyrimethamine, phenedione, sulfisoxazole, sulfadiazine, temazepam, sulfamerazine, trioxsalene. Examples of pharmaceutically active hydrophilic substances include, but are not limited to, 17p-estradiol, acyclovir, estriol, raloxifene, pravastatin, atenolol, aminoglycosides, polysaccharide, cyclodextrins and chitosan.

In the present case, the hydrophilicity of a drug or a block of copolymer is determined by the solubility in water at 25 ° C. If a chemical has a solubility value of less than 0.01 mg / ml in water at 25 ° C, it is considered hydrophobic. If a chemical has a solubility value of more than 0.01 mg / m in water at 25 ° C, it is considered to be hydrophilic.

In one embodiment, the drug delivery devices comprise an anti-HIV agent selected from the group consisting of non-nucleoside reverse transcriptase inhibitors, reverse transcriptase inhibitors nucleoside and HIV entry inhibitors. Preferably, the non-nucleoside reverse transcriptase inhibitor is UC 781 and / or the nucleoside reverse transcriptase inhibitor is tenofovir.

The present drug delivery devices comprise at least two pharmaceutically active substances in a single copolymer having contrasted hydrophilicities. Thus, the drug delivery device has been developed for the co-contribution of pharmaceutically active substances with hydrophilicity contrasted from a polymer. The drug delivery device may be a mechanical device, such as an intravaginal ring. The drug delivery devices are adapted to support pharmaceutically active substances with proven hydrophilicity from a polyurethane copolymer that forms a single segment drug delivery device. In the case of intravaginal rings, the single-segment IVR device must be manufactured more easily and less expensively than the multi-segment IVR (see Todd J. Johnson, et al., "Segmented polyurethane intravaginal rings for the sustained combined delivery of antiretroviral agents dapivirine and tenofovir "European Journal of Pharmaceutical Sciences 39 (2010) 203-207, which describes two drugs, dapivirine and tenofovir, with proven hydrophilicity provided from a dual-segment IVR device. The two drugs were formulated separately in polyurethanes with matching hydrophilicity. The bars loaded with drug joined together to form double segment IVRs).

In one embodiment, the amount of pharmaceutically active substance to be incorporated into the drug delivery devices ranges from about 0.005 to about 65% by weight relative to the total weight of the polyurethane copolymer in the drug delivery device, and more preferably it ranges from about 0.2% by weight to about 30% by weight of the polyurethane copolymer in the drug delivery device. The amount of pharmaceutically active substance incorporated can also be calculated as a pharmaceutically effective amount, where the devices of the present polyurethane copolymer comprise a pharmaceutically effective amount of one or more pharmaceutically active substances. By "pharmaceutically effective" is meant an amount that is sufficient to effect the desired physiological or pharmacological change in a subject. This amount will vary depending on factors such as the potency of the particular pharmaceutically active substance, the desired physiological or pharmacological effect and the time span of the intended treatment. Those skilled in the pharmaceutical techniques will be able to determine the pharmaceutically effective amount for any pharmaceutically active substance given according to the standard procedure. In some embodiments, the pharmaceutically active substance is present in an amount ranging from about 2 mg to about 300 mg of pharmaceutically active substance per gram of polyetherurethane. This includes embodiments in which the amount ranges from about 2 mg to about 50 mg, from about 50 mg to about 150 mg and from about 150 mg to about 300 mg of pharmaceutically active substance per gram of polyetherurethane.

The drug delivery device according to the invention comprises at least one polyurethane copolymer with a structure according to formula (I).

The soft segments of the polyurethane copolymer according to formula (I) comprise a diol. A diol is an alcohol that contains at least two hydroxyl groups. A diol is a polymeric soft segment that distinguishes itself from short chain or low molecular weight chain extenders. The soft segment diols of the polyurethane copolymers of the present invention contain at least two hydroxyl groups. Examples of polyether diols (SS1), which are considered hydrophilic diols, are PEOdiol, PTMOdiol, PPOdiol, diol copolymer of PPO-co-PEO. Examples of hydrophobic diols include silicone diols (SS2), polyester diols or polycarbonate diols (SS3).

In general, the number average molecular weights of the soft segments vary from 500 to 5000 g / mol.

In the present polyurethane copolymers, there are three blocks comprising the soft segment; SS1, SS2 and SS3. The relationship of the soft segments can characterize the structural peculiarities of the present polymers. For example, if x = 0, y = 1 and z = 2, then SS1 is not present and the ratio of SS3 to SS2 is 2 to 1. In one embodiment, SS1 is a polyetherdiol selected from PEOdiol, PTMOdiol, poly (oxide of hexamethylene diol (PHMO), PPOdiol, copolymer of ethylene glycol and propylene glycol (diol of PEG-co-PPO) and mixtures thereof.

The PEOdiol can be a linear PEOdiol or a side chain PEOdiol. The side chain PEOdiol can be YMER®N120.

In one embodiment, SS2 is a silicone polymer terminated in hydroxyl or amine.

The addition of soft silicone segments that are hydrophobic in nature can modify the release characteristics of the drug. Soft silicone segments include silicone oils that have a number average molecular weight ranging from 500 to 5000 g / mol. Examples of which may include silicone polymers prepared by using silicones such as Shin22ts X22-160AS (Molecular Weight ~ 1000) and MCR-C61 (Molecular Weight ~ 1000) or PDS-1615 (Molecular Weight ~ 900-1000) of Gelest.

The percentage of the soft silicone segment may be up to 40% by weight, or more preferably it may be up to 20% by weight of the total weight of the polyurethane copolymer.

SS3 is a distinct soft segment of polyether and silicone and is selected from polycarbonate diol, polyester ether and mixtures thereof.

In one embodiment, the polyurethane copolymer comprises at least two different soft segments.

In the polyurethane copolymers, the hard segment, HS, can be made from the diisocyanate and chain extender reaction, wherein the diisocyanate is selected from the group consisting of hexamethylene diisocyanate (HMDI) and isophorone diisocyanate (IPDI ) and combinations thereof. For the purpose of polyurethane copolymers according to formula 1, a diisocyanate is a molecule with two isocyanate functional groups, R- (N = C = O) n = 2.

The diisocyanates can be aromatic or aliphatic diisocyanates. Aliphatic diisocyanates are used in polyurethane copolymers according to the invention. Aliphatic diisocyanates include, but are not limited to, hexamethylene diisocyanate (HMDI) and isophorone diisocyanate (IPDI) and combinations thereof.

A chain extender can be selected from a diol, a diamine or a short chain amino alcohol having a number average molecular weight ranging from 32 to 500 g / mol, or it can be a side chain PEO in which the diol it is on one side of the molecular chain, such as in YMER® N120, which has a number average molecular weight ranging from 500 to 3000 g / mol, and mixtures thereof. Examples of the cut-chain diol include, but are not limited to, ethylene glycol, 1,4-butanediol (1,4-BDO or BDO), 1,6-hexanediol, cyclohexanedimethanol and hydroquinone bis (2-hydroxyethyl) ether (HQEE ).

In one embodiment, the percentage of the hard segment may vary from 20 to 45% by weight of the total weight of the polyurethane copolymer.

The polymers according to the invention comprise a surface modifying agent or a surface modifying end group (SME), in the polymer. A surface modifying end group is an end group that rearranges its placement in a polymer body to the position of the end group of the body depending on the composition of the medium with which the body is in contact.

The SME group used in the polyurethane copolymers according to the present invention is methylpolyethylene glycol (MPEG). The end groups migrate to the surface of a device and thereby introduce a biocompatible surface without compromising the mass properties of the polymer. For example, MPEG dominates the surface of the IVR, which results in an antifouling surface and facilitates drug release by reducing deposit formation. x, y and z in Formula I are integers equal to or greater than zero. Preferred whole numbers are greater than zero and less than 700, preferably less than 200. At least one of x, y and z in formula 1 is not equal to zero.

In one embodiment, the polyurethane copolymer comprises 15-35% by weight of at least one soft segment, 20-40% by weight of at least one hard segment and 0-2% by weight of a surface modifying end group; all referred to the total weight of the dry polyurethane copolymer.

In one embodiment of the invention, the polyurethane copolymers in the drug delivery device are capable of absorbing water up to 50% by weight relative to the total weight of the dry copolymer.

Antioxidants and other additives may be added to the present polyurethane copolymers in the drug delivery device. Examples of antioxidants include but are not limited to 3- (3,5-di-tert.butyl-4-hydroxyphenyl) octadecyl propionate (Irganox®), ethylenediaminetetraacetic acid (EDTA), butylated hydroxytoluene (BHT), citric acid ( CA), butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ) and propyl gallate (PG).

In one embodiment, the polydispersity index (Mw / Mn) of the present urethane copolymers can vary from about 1.5 to 2.5.

Polyurethanes are biocompatible. By biocompatible it is understood that a biomaterial is capable of performing its desired function with respect to medical therapy, without causing undesirable local or systemic effects in the recipient.

Specifically, the present polyurethanes are acitotoxic for a vaginal cell line such as Vk2.

The polyurethane copolymers used in the drug delivery devices according to the invention are produced in a polyurethane production process.

The process involves producing polyurethanes by reacting polyaddition of one or more diisocyanates with one or more diols, one or more chain extenders and one or more surface modifying end groups in the presence of a catalyst. The reaction product is a polymer that contains the urethane bond, -RNHCOOR'-. A generalized polyurethane reaction is as shown below:

The catalyst may include organotin compounds, bismuth compounds, organic and inorganic bases and combinations thereof. Specific examples include dibutyltin dilaurate, stannous octoate and combinations thereof. The catalyst is preferably stannous octoate.

The polyurethane copolymer is combined with at least one pharmaceutically active substance or pharmaceutically active substances having proven hydrophilicity to form a polyurethane copolymer loaded with pharmaceutically active substance. The methods include combining the polyurethane with the pharmaceutically active substances, dissolving both the polyurethane and the pharmaceutically active substances in solution followed by evaporation of the solvent.

The extrusion conditions of the polyurethane copolymers are below 240 ° C, preferably below 160 ° C and more preferably between 128 ° C-155 ° C in order to retain the stability of the pharmaceutically active substance for pharmaceutically active substances thermolabile Polyurethane copolymers comprising aliphatic diisocyanates can be extruded at these low temperatures.

The polyurethane copolymer loaded with pharmaceutically active substance is formed in conformations suitable for use in drug delivery, wherein a pharmaceutically effective amount of at least two pharmaceutically active substances having proven hydrophilicity is homogeneously distributed throughout the copolymer. This can be accomplished under a variety of conditions, including, but not limited to, those described in Example 1.

The polyurethane copolymer forms a polymeric matrix and, preferably, the polymeric matrix forms a monolithic system. Thus, a single segment monolithic drug delivery device can be formed from the polyurethane copolymer.

The polyurethane copolymer loaded with pharmaceutically active substance is formed in a conformation suitable for use in the intravaginal delivery of drugs, wherein a pharmaceutically effective amount of at least one pharmaceutically active vaginally administrable substance is combined with the polyurethane copolymer. In some embodiments in which the device is an intravaginal ring, the step of forming the polyetherurethane copolymer loaded with pharmaceutically active substance in the shaping of the device involves extruding the polyurethane copolymer loaded with pharmaceutically active substance into a rod and joining the ends of the extruded bar to form a ring. The ends of the ring can be joined together through a variety of biocompatible adhesives, including, but not limited to, polyurethane free of pharmaceutically active substance or loaded with molten pharmaceutically active substance. Each of these stages can be carried out under a variety of conditions.

The drug delivery devices of the present invention may encompass a variety of conformations and sizes with the proviso that the device is compatible with internal administration to the subject and with the requirements imposed by the drug input kinetics. The dimensions of the device may vary depending on the mode of administration, the anatomy of the subject, the amount of pharmaceutically active substance to be provided to the patient, the time over which the pharmaceutically active substance is to be provided, the characteristics. of diffusion of the pharmaceutically active substance and other manufacturing considerations. The device is for intravaginal administration. This includes embodiments in which the device is in the form of an intravaginal ring (IVR) or is in annular form. The IVR should be flexible enough to allow curvature and insertion into the vaginal cavity and rigid enough to withstand the expulsive forces of the vaginal musculature without causing abrasion to the vaginal epithelium. In some embodiments, the cross-sectional diameter of the IVRs may vary, e.g. eg, from about 3 mm to about 10 mm. Other intravaginal devices include tablets, pessaries, bars and films for adhesion to the mucous epithelium such as those disclosed in US Pat. UU. Number 6,951,654, which is hereby incorporated by reference in its entirety.

The present polyurethane drug delivery devices demonstrate release characteristics that are adapted to fit a range of suitable pharmaceutically active substances, to provide sustained release of pharmaceutically effective amounts of pharmaceutically active substances in the desired use space. Specifically, pharmaceutically active substances may include UC781, tenofovir (TFV) and levonorgestrel (LNG) alone or in combination, including the combination of pharmaceutically active substances with proven hydrophilicity (eg UC781 and tenofovir) to be provided from an intravaginal drug delivery device and provide a range of delivery rates for a particular pharmaceutically active substance. The release rate can be controlled through the percentage of hard segment, the ratio of the hydrophilic segment to the hydrophobic segment of the polyurethane and the selection of the diisocyanate.

In one embodiment, the release rate of a pharmaceutically active substance is determined by a value of the daily flow. Preferably, the average daily flow of at least one of the pharmaceutical active substances is greater than 0.1 pg / mm2 / d.

Unlike the bioabsorbable drug delivery device, the device of the invention comprises a biostable polymer used as a matrix to disperse or dissolve the drug inside. Thus, the polymer needs to withstand mechanical integrity and physical stability.

Properties that are desired for intravaginal drug delivery devices include mechanical properties, drug release properties, biostability and biocompatibility for the intended duration of implantation. The mechanical properties (dry and swollen hardness, tensile strength, modulus, percent elongation at breakage) of an IVR material are crucial for the efficacy and acceptability of IVR in vivo. An IVR that is too stubborn may be difficult to insert and could cause tissue damage and inflammation. (See Bounds, W., Szarewski, A., Lowe, D., Guillebaud, J., 1993. Preliminary report of unexpected local reactions to a progestogen-releasing contraceptive vaginal ring. Eur. J. Obstet. Gynecol. Reprod. Biol 48, 123-125 and Weisberg, E., Fraser, IS, Baker, J., Archer, D., Landgren, BM, Killick, S., Soutter, P., Krause, T., D'arcangues, C ., 2000 A randomized comparison of the effects on vaginal and cervical epithelium of a placebo vaginal ring with nonuse of a ring. Contraception 62, 83-89.) While a ring that is too soft may lack retention and thus slip or be expelled from the vagina (Koetsawang, S., Ji, G., Krishna, U., Cuadros, A., Dhall, GI, Wyss, R., Rodriquez La Puenta, J., Andrade, AT, Khan, T., Kononova, ES, et al., 1990. Intravaginal microdose levonorgestrel contraception: a multicenter clinical trial. III. The relationship between pregnancy rate and body weight. World Health Organization. Task force on long-acting systemic agents for ferti lity regulation. Contraception 41, 143 150). Since the device is used in a vaginal environment, it is important that the polymer show desired mechanical properties after the polymer is swollen by the vaginal fluid. Therefore, the hardness in swollen state (in pH 4.0 buffer that simulates the vaginal environment) of the polymer was also one of the design criteria.

Intravaginal devices should be able to provide sustained release of one or more pharmaceutically active substances during the desired use space. The drug release rate is affected by the equilibrium swelling percentage of the polymer. For example, for a hydrophilic pharmaceutically active substance, the release rate should be increased with the increase in the equilibrium swelling percentage of the polymer.

A further embodiment of the invention is a method for administering one or more pharmaceutically active substances to a patient in need, which comprises inserting the drug delivery device into the patient, thereby the active substance is released from the delivery device while The device resides in the body of a subject.

The invention will now be illustrated by the following non-limiting examples.

Examples

Mechanical properties that are desired for medical devices in general include hardness, tensile strength, modulus, percent elongation at break.

The hardness can be measured either dry or with swollen polymers. In any case, the hardness must be at least 30A. The dry hardness may preferably vary from 40A-45D. The hardness in swollen state may preferably vary from 30A to 90A. The hardness of the polymer is measured by the Shore® test. Shore hardness is measured with an apparatus known as a hardness tester and therefore also known as 'hardness per hardness meter'. The hardness value is determined by penetration of the insertion leg into the sample.

The tensile strength of the present polymers may vary from 0.8 MPa to 37.2 MPa (from 115.0 psi to 5400.0 psi). A preferred tensile strength is at least 3.4 MPa (500 psi).

A measure of tenacity can be Young's modulus.

Properties that are desired for intravaginal drug delivery devices include mechanical properties, drug release properties, biostability and biocompatibility for the intended implantation duration.

Example 1: Synthesis of polyurethanes

Several items of polyurethane material were synthesized by varying the formulation of each item (Table 1). Composition changes made in the various items include 1) using either isophorone diisocyanate (IPDI) or hexamethylene diisocyanate (HMDI) such as aliphatic isocyanate, 2) changing the percentage of hard segment, 3) using different amounts of soft segment of methoxypolyethylene glycol (MPEG), 4) soft silicone segment inclusion, and 5) varying the catalyst.

The polyurethane was synthesized in a batch reactor. A discontinuous synthesis of the polyurethane material involved adding the required amount of polyols, aliphatic diisocyanate and catalyst to a 0.5 l (1 pint) glass jar equipped with a mechanical stirrer, heating the jar to 100 ° C for 3 hours followed by adding the required amount of a surface modifying end group and continue heating at the same temperature for 2 hours. Chain extension was achieved by the addition of butanediol, after which the polymeric material was poured into plastic trays and cured at 100 ° C for 24 hours. Next, the hardened polymer plate was crushed into smaller granules to combine with pharmaceutically active substances.

Example 2: Mw, swelling, mechanics, polyurethane processing temperature

The analytical results of the various polyurethane items are summarized in Table 1. It was found that most of the polyurethane items met the criteria for Mw, swelling and dry mechanical properties that were desirable for IVR devices. The polyurethanes were combined with 20% tenofovir (TFV) and 5% UC781. Most items combined with TFV and UC781 show a 2-3-fold reduction in the elastic modulus when hydrated. In addition, the results also showed that polyurethanes according to lot No. 1100032, 1100235, 1100048 and 1100234 could be used to design an IVR that had mechanical properties (25% compression strength of IVR) similar to IVRs already in use such as NuvaRing with an acceptable transverse IVR diameter (~ 5-9 mm).

Example 3: Combination of polyurethane matrices loaded with TFV and UC781

The polyurethanes were combined with 20% TFV and 5% UC781. As an example, items 1100234 and 1100235 were combined with 20% TFV and 5% UC781 and extruded to cylindrical wires of 5 mm in cross section. The extrusion temperatures for 1100234 and 1100235 were 128 ° C and 134 ° C, respectively. Segments of approximately 10-20 mm in length were incubated in 25 mM sodium acetate buffer with 2% Solutol HS-15 (pH = 4.2) (changed daily) at 37 ° C and 80 rpm on a heated stirrer for 7 days. Samples of release media were taken, taken after 24 ± 1 h of incubation and stored at -80 ° C. Samples were analyzed using a gradient 25-minute HPLC method (potassium phosphate and acetonitrile pH = 6). Using the model y = a * (1 + x) Ab, the release data was adjusted to a continuous profile, whose equation was used to determine the average daily flow. The release data represent N = 3 bars, mean ± standard deviation (SD).

Example 4: Polyurethane drug release studies loaded with TFV and UC781

Segments approximately 15 mm long were incubated in 25 mM sodium acetate buffer with 2% Solutol HS-15 (pH = 4.2) (changed daily) at 37 ° C and 80 rpm on a heated stirrer for 30 days. Samples of release media were taken, taken after 24 ± 1 h of incubation and stored at -80 ° C. For lots '68' and '40', equal volumes of each aliquot were mixed in an HPLC vial to represent the average daily concentration of each analyte. For all other materials, aliquots from three moments throughout the release study were analyzed by HPLC. Using the model y = a * (1 + x) Ab, the release data was adjusted to a continuous profile, whose equation was used to determine the average daily flow. The release data represents N = 3 bars, mean ± SD.

The results showed that the flow of UC781 is 2-3 gg / mm2 / d and is minimally affected by the polymer composition; the TFV flow varied from 2-23 gg / mm2 / d and correlated with 1) the degree of swelling, 2) the percentage of hard segment, and 3) the silicone content. It was found that the initial drug release release increased with the increasing hardness of the material material. This was both surprising and unexpected. In general, the initial drug release release was expected to decrease with the increasing hardness of the polyurethane.

Example 5 Study of processing stability and accelerated stability of polyurethanes loaded with TFV and UC781

Lot 1100032 was combined with TFV and UC781 and it was found that the Mw decreased to 58% of the initial value after extrusion (Table 2). The decrease in molecular weight of Lot No. 1100032 may be caused mainly by the relatively high water content of the polymer before being extruded and the TFV (20% by weight in PU) which is a monohydrate that tends to facilitate hydrolysis of the PU material. Various antioxidants were incorporated in lot 1100032 in order to improve the stability of the process, and it was found that the Mw was still reduced to 39-61% of the original value with antioxidants (Table 2). The results suggest that antioxidants do not improve the process stability of polyurethanes combined with drugs.

In addition to the processing stability studies, an accelerated stability study was also carried out on Lot 1100032 combined with TFV and UC781, with various antioxidants added. Samples were extracted after ~ 2.5 months and the stability of Lot 1100032 was evaluated by Mw analysis. It was found that the Mw barely changed after the accelerated stability study of ~ 2.5 months compared to the control (t = 0) for all antioxidants. The results suggest that Lot 1100032 was stable under accelerated storage conditions in the presence of drugs and antioxidants.

Example 6 Stability of drugs in polyurethanes loaded with TFV and UC781

The stability of the drugs in Lot 1100032 combined was also studied after extrusion and under accelerated storage conditions, with and without various antioxidants (Table 3). The results suggest that the process flow temperature (128 ° C-155 ° C) of the polyurethanes was low enough to retain the stability of UC781 after extrusion. Data from 60 ° C at 4-5 weeks showed that Irganox is incompatible with UC781. UC781 showed the best stability with BHT, EDTA or without additives.

Example 7 Cytotoxicity of polyurethanes

50 ± 5 mg of cylindrical segments of extruded polymer (simple extrusion, no cryotriting, no drying) were immersed in 70% isopropanol for 5 seconds and air dried for about an hour in a laminar flow hood. The bars were transferred to microcentrifuge tubes and incubated in 1.5 ml of keratinocyte-SF cells medium. The tubes were allowed to rotate in the microcentrifuge at a "8" graduation for 24 h at room temperature. Latex fragments (6-7 per tube measuring 5 mm x 2 mm) were also incubated in 1.5 ml of medium / tube. N-9 (conc. 49.6 pM) was prepared in medium. Vk2 cells were seeded at a density of 40,000 cells per well (96-well format) and incubated for 24 h (37C, 5% CO2). 300 pl of medium from each centrifuge tube containing cylinders and containing latex (N = 6) are added to the cells. 300 p of N-9 are also added to the cells in medium (N = 6). The cells were incubated for 24 h. A cell viability analysis was performed using the Cell Titer 96 Aqueous Non-Radioactive Cell Proliferation Assay (MTS assay).

It was found that (see Table 1) the preliminary items prepared with dibutyltin dilaurate as a catalyst were cytotoxic for a vaginal cell line (eg, Lot No. 1100032). In subsequent items (e.g., Lot No. 1100121), dibutyltin dilaurate was replaced by stannous octoate and the items were found to be acitotoxic. The results suggest that dibutyltin dilaurate is the cause of cytotoxicity for the items using this catalyst.

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Table 3. Stability of UC781 in Lot 1100032 with and without additives

Claims (15)

1. An intravaginal drug delivery device comprising at least two pharmaceutically active substances, in which the pharmaceutically active substances have proven hydrophilicity, combined with a polyurethane copolymer, wherein the copolymer has the structure according to formula (I):

in which, SME1 and SME2 may be the same or different and indicate a surface modifying end group, which has a number average molecular weight ranging from 200 to 8000 g / mol, connected to the polymer through a urethane or urea bond resulting from the reaction of a surface modifying end group terminated in amine or alcohol with an isocyanate group, wherein SME1 and SME2 are methylpolyethylene glycol; SS1, SS2 and SS3 indicate soft segments, in which 551 is a polyetherdiol selected from poly (ethylene oxide) (PEO) diol, poly (tetramethylene oxide) (PTMO) diol, poly (hexamethylene oxide) diol (PHMO), poly (propylene oxide) (PPO) diol, ethylene glycol and propylene glycol diol copolymer (PEG-co-PPO), and mixtures thereof; 552 is a silicone polymer terminated in hydroxyl or amine having a number average molecular weight ranging from 500 to 5000 g / mol; Y 553 is a soft segment selected from polycarbonate diol and polyester ether, and mixtures thereof; HS indicates a hard segment prepared from the reaction of one or more diisocyanates and one or more chain extenders, wherein the diisocyanate is selected from the group consisting of hexamethylene diisocyanate (HMDI) and isophorone diisocyanate (IPDI) and combinations thereof; x, y and z are the same or different and each is an integer equal to or greater than zero and at least one of x, y and z is not zero; Y wherein the copolymer has a number average molecular weight ranging from 50,000 to 350,000 g / mol. 2. Device according to claim 1, wherein the pharmaceutically active substances are tenofovir and UC781. 3. Device according to any one of claims 1-2, wherein at least one of the pharmaceutically active substances is homogeneously distributed through the polyurethane copolymer. 4. Device according to claim 3, wherein two or more pharmaceutically active substances are homogeneously distributed through the polyurethane copolymer. 5. Device according to any one of claims 1-4, wherein the polyurethane copolymer comprises at least two different soft segments. 6. Device according to any one of claims 1-5, wherein the polyurethane copolymer comprises 15-35% by weight of at least one soft segment, 20-40% by weight of at least one hard segment and 0-2 % by weight of a surface modifying end group; all in relation to the total weight of the dry polyurethane copolymer. 7. Device according to any one of claims 1-6, wherein the device is a monolithic polymer device. 8. Device according to claim 7, wherein the device is an intravaginal ring. 9. Device according to any one of claims 1-8, wherein the Shore hardness of the copolymer after swelling in pH 4.0 buffer is at least 30A. 10. Device according to claim 1, wherein the polyurethane copolymer is capable of absorbing water up to 50% by weight relative to the total weight of the dry copolymer. 11. Device according to any one of claims 1-10, wherein the polyurethane composition is made by a process in which the catalyst used is stannous octoate. 12. Device according to any one of claims 1-11, further comprising antioxidants. 13. Device according to any one of claims 1-12, wherein the polymer is acitotoxic. 14. Device according to claim 1, wherein the percentage of the soft silicone segment is up to 40% by weight of the total weight of the polyurethane copolymer. 15. Device according to claim 1, wherein the percentage of the soft silicone segment is up to 20% by weight of the total weight of the polyurethane copolymer.